Bretaris® genueair®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bretaris® Genuair® (Bretaris® Genuair®)

Composition:

Active substance: aclidinium bromide;

1 delivered dose (dose exiting the mouthpiece) contains 375 mcg of aclidinium bromide, equivalent to 322 mcg of aclidinium. This corresponds to a metered dose of 400 mcg of aclidinium bromide, equivalent to 343 mcg of aclidinium;

Excipient: lactose monohydrate.

Pharmaceutical form. Inhalation powder.

Main physicochemical properties: white or almost white, fine granular free-flowing powder without visible agglomerates or foreign particles.

Pharmacotherapeutic group.
Agents for treatment of obstructive airway diseases, anticholinergic agents. ATC code R03BB05.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Aclidinium bromide is a competitive, selective antagonist of muscarinic receptors (anticholinergic agent) with a longer duration of binding to M3 receptors than to M2 receptors. M3 receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs as an antagonist of M3 receptors on airway smooth muscle, resulting in bronchodilation. Preclinical studies in vitro and in vivo demonstrated rapid, dose-dependent, and prolonged inhibition by aclidinium of acetylcholine-induced bronchospasm. Aclidinium bromide is rapidly degraded in blood plasma; therefore, the number of systemic anticholinergic adverse reactions is low.

Pharmacodynamic effect.

Clinical efficacy studies showed that Bretaris**®** Genair**®** provides clinically meaningful improvement in lung function (measured by forced expiratory volume in 1 second [FEV1]) over 12 hours after both morning and evening dosing, evident within 30 minutes after the first dose (increase in FEV1 from baseline was 124–133 mL). Maximum bronchodilation was achieved within 1–3 hours after dosing, with a mean peak improvement in FEV1 from baseline of 227–268 mL at steady state.

Cardiac electrophysiology.

No effect on QT interval (corrected by Fridericia or Bazett methods or individually corrected) was observed when aclidinium bromide (200 mcg or 800 mcg) was administered once daily for 3 days to healthy subjects.

Additionally, no clinically significant effect of Bretaris**®** Genair**®** on heart rhythm was observed during 24-hour Holter monitoring after 3 months of treatment in 336 patients (164 of whom received Bretaris**®** Genair**®** twice daily at 322 mcg).

Clinical efficacy and safety.

The phase III clinical development program included 269 patients who received Bretaris**®** Genair**®** 322 mcg twice daily in a 6-month placebo-controlled randomized trial, and 190 patients who received Bretaris**®** Genair**®** 322 mcg twice daily in a 3-month placebo-controlled randomized trial. Efficacy was assessed by lung function and symptomatic outcomes such as dyspnea, disease-specific health status, use of rescue medication, and exacerbation rates. In long-term safety studies, Bretaris**®** Genair**®** demonstrated bronchodilator efficacy for more than 1 year.

Bronchodilation.

In a 6-month study in patients receiving Bretaris**®** Genair**®** 322 mcg twice daily, clinically meaningful improvement in lung function (measured by FEV1) was observed. Maximum bronchodilator effect was evident from day 1 and increased over the 6-month treatment period. After 6 months of therapy, the mean improvement in pre-morning dose (trough) FEV1 compared to placebo was 128 mL (95% CI 85–170; p < 0.0001).

Similar observations were made for Bretaris**®** Genair**®** in 3-month studies.

Bretaris**®** Genair**®** provided clinically meaningful reduction in dyspnea (assessed by the Transition Dyspnea Index [TDI]), with a TDI improvement of 1.0 unit compared to placebo after 6 months of treatment (p < 0.001).

The percentage of patients achieving clinically significant improvement in TDI (defined as an increase of at least 1 unit in TDI score) was higher in the Bretaris**®** Genair**®** group compared to placebo (56.9% vs. 45.5%; p = 0.004).

Bretaris**®** Genair**®** demonstrated clinically meaningful symptom relief with improvement in overall health status compared to placebo—4.6 units (p < 0.0001). The percentage of patients achieving clinically significant improvement from baseline was higher in the Bretaris**®** Genair**®** group compared to placebo (57.3% vs. 41.0%; p < 0.001).

Patients receiving Bretaris**®** Genair**®** required fewer rescue medications than those receiving placebo (reduction of 0.95 puffs per day over 6 months [p = 0.005]). Bretaris**®** Genair**®** also improved daytime symptoms of chronic obstructive pulmonary disease (COPD) (dyspnea, cough, and sputum production), as well as nighttime and early morning symptoms.

A pooled analysis of efficacy from 6-month and 3-month placebo-controlled trials demonstrated a significant reduction in the frequency of moderate and severe exacerbations (requiring treatment with antibiotics or corticosteroids or resulting in hospitalization) with 322 mcg aclidinium twice daily compared to placebo.

Long-term safety and efficacy study with up to 3 years of treatment.

The effect of aclidinium bromide on the occurrence of major adverse cardiovascular events (MACE) was evaluated in a randomized, double-blind, placebo-controlled, parallel-group study involving 3630 adult patients aged 40 to 91 years with moderate to very severe COPD, treated for up to 36 months. Of these, 58.7% were male, 90.7% were of Caucasian race, with a mean post-bronchodilator FEV1 of 47.9% of predicted value and a mean COPD Assessment Test (CAT) score of 20.7. All patients had a history of cardiovascular or cerebrovascular disease and/or significant risk factors for cardiovascular disease. 59.8% of patients had experienced at least one COPD exacerbation in the 12 months prior to screening. Approximately 48% of study participants had a documented cardiovascular event in their history: cerebrovascular disease (13.1%), coronary artery disease (35.4%), peripheral vascular disease or claudication (13.6%).

The study had an event-driven design and was terminated upon reaching a sufficient number of MACE events for primary safety analysis. Upon occurrence of MACE, treatment was discontinued and patients were transferred to a post-treatment observation group. According to investigator assessment, 70.7% of patients completed the study. The mean treatment duration in the Bretaris**®** Genair**®** and placebo groups was 1.1 and 1.0 years, respectively. The mean duration of participation in the study was approximately 1.4 and 1.3 years in the Bretaris**®** Genair**®** and placebo groups, respectively.

The primary safety endpoint was time to first occurrence of MACE, defined as any of the following confirmed events: cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal ischemic stroke. The incidence of at least one MACE was 3.85% and 4.23% in the aclidinium and placebo groups, respectively. Treatment with Bretaris**®** Genair**®** did not increase the risk of MACE in patients with COPD compared to placebo when added to background therapy (hazard ratio [HR] 0.89; 95% CI: 0.64, 1.23). The upper limit of the confidence interval excludes a risk margin of 1.8.

The rate of moderate or severe COPD exacerbations per patient per year during the first year of treatment was evaluated as the primary efficacy endpoint. Patients receiving Bretaris**®** Genair**®** showed a statistically significant 22% reduction compared to placebo (rate ratio [RR] 0.78; 95% CI: 0.68, 0.89; p < 0.001). Furthermore, treatment with Bretaris**®** Genair**®** resulted in a statistically significant 35% reduction in hospitalization rates due to COPD exacerbations during the first year compared to placebo (RR 0.65; 95% CI: 0.48, 0.89; p = 0.006).

In the group receiving Bretaris**®** Genair**®**, the time delay to the first moderate or severe exacerbation was statistically significantly prolonged compared to the placebo group. In the aclidinium bromide group, a relative 18% reduction in exacerbation risk was observed (HR 0.82; 95% CI [0.73, 0.92], p < 0.001).

Exercise tolerance.

In a 3-week crossover, randomized, placebo-controlled clinical trial, treatment with Bretaris**®** Genair**®** was associated with a statistically significant improvement in exercise endurance compared to placebo by 58 seconds. Bretaris**®** Genair**®** significantly reduced resting lung hyperinflation, increased inspiratory volume, and reduced dyspnea during exercise.

Pharmacokinetics.

Absorption.

Aclidinium bromide is rapidly absorbed from the lungs, reaching peak plasma concentration within 5 minutes after inhalation in healthy subjects and typically within the first 15 minutes in patients with COPD. The fraction of the inhaled dose reaching systemic circulation as unchanged aclidinium was very low, less than 5%.

At steady state, peak plasma concentration achieved in COPD patients after inhalation of 400 mcg aclidinium bromide dry powder was approximately 224 pg/mL. Steady-state plasma levels were achieved within 7 days with twice-daily dosing.

Distribution.

The total amount of aclidinium bromide inhaled via the Bretaris**®** Genair**®** inhaler that reaches the lungs is approximately 30% of the metered dose.

Plasma protein binding of aclidinium bromide in vitro is likely attributable to metabolite binding due to rapid hydrolysis of aclidinium bromide in plasma. Plasma protein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The main plasma protein binding aclidinium bromide is albumin.

Biotransformation.

Aclidinium bromide is rapidly and actively hydrolyzed to its pharmacologically inactive alcohol and carboxylic acid derivatives. Both chemical (non-enzymatic) and enzymatic hydrolysis (mediated by esterases) occur. The main esterase involved in hydrolysis in humans is butyrylcholinesterase. Plasma levels of the acid metabolite after inhalation are approximately 100 times higher than those of the alcohol metabolite and unchanged active substance. The low absolute bioavailability of aclidinium bromide after inhalation (< 5%) is due to active systemic and presystemic hydrolysis in both the lungs and gastrointestinal tract. CYP450 enzyme-mediated biotransformation plays a negligible role in the overall metabolic clearance of aclidinium bromide.

In vitro studies showed that aclidinium bromide at therapeutic doses or its metabolites do not inhibit or induce any cytochrome P450 (CYP450) enzymes and do not inhibit esterase activity (carboxylesterase, acetylcholinesterase, and butyrylcholinesterase). In vitro studies also showed that aclidinium bromide or its metabolites are not substrates or inhibitors of P-glycoprotein.

Elimination.

In patients with COPD, after twice-daily inhalation of 400 mcg, the terminal and effective half-lives of aclidinium bromide are approximately 14 hours and 10 hours, respectively.

After intravenous administration of 400 mcg radiolabeled aclidinium bromide to healthy volunteers, about 1% of the dose was excreted unchanged in urine. Up to 65% of the dose was excreted as metabolites in urine and up to 33% as metabolites in feces.

After inhaled administration of 200 mcg and 400 mcg aclidinium bromide to healthy subjects and COPD patients, a very small amount—approximately 0.1% of the administered dose—was excreted unchanged in urine, indicating that renal clearance plays a negligible role in the overall clearance of aclidinium from plasma.

Linearity/Non-linearity.

Aclidinium bromide demonstrated linear kinetics and time-independent pharmacokinetics within the therapeutic range.

Special patient populations.

Patients with hepatic impairment.

Studies in patients with hepatic impairment have not been conducted. Since aclidinium bromide is primarily metabolized via chemical and enzymatic degradation in plasma, it is highly unlikely that hepatic impairment alters its systemic exposure. Dose adjustment is not required for COPD patients with hepatic impairment.

Elderly patients.

Pharmacokinetic properties of aclidinium bromide in COPD patients with moderate to severe disease are similar in patients aged 40–59 years and those over 70 years of age. Therefore, dose adjustment is not required for elderly COPD patients.

Patients with renal impairment.

No significant differences in pharmacokinetics were observed between patients with normal renal function and those with renal impairment. Therefore, dose adjustment and additional monitoring are not required for COPD patients with renal impairment.

Race.

Similar systemic exposure to aclidinium bromide after repeated inhalations was observed in Japanese and Caucasian subjects.

Pharmacokinetic/pharmacodynamic relationship.

Since aclidinium bromide acts locally in the lungs and is rapidly degraded in plasma, there is no direct relationship between pharmacokinetics and pharmacodynamics.

Preclinical safety data.

Preclinical safety data based on conventional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity studies revealed no special risks to humans. In preclinical studies, cardiovascular effects (increased heart rate in dogs), reproductive toxicity (fetotoxic effects), and fertility effects (slight reduction in conception rate, number of corpora lutea, and pre- and post-implantation embryonic loss) were observed only at exposure levels significantly exceeding the maximum human exposure, indicating limited relevance for clinical use. The low toxicity observed in preclinical toxicity studies is partly due to the rapid metabolism of aclidinium bromide in plasma and the lack of significant pharmacological activity of most metabolites. The safety margin for systemic exposure at 400 mcg twice daily in these studies ranged from 7- to 73-fold above the maximum dose not associated with observed adverse effects.

Clinical characteristics.

Indications.

Maintenance bronchodilator therapy to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adult patients (see section "Pharmacodynamics").

Contraindications.

Hypersensitivity to aclidinium bromide or to any of the excipients.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of aclidinium bromide with other anticholinergic medicinal products is not recommended, as it has not been studied. Although formal in vivo drug interaction studies have not been conducted, aclidinium bromide administered by inhalation has been used together with other medicinal products for COPD therapy, including bronchodilators: sympathomimetics, methylxanthines, and steroids – administered by inhalation or orally, without clinical evidence of drug interactions. In vitro studies have demonstrated that aclidinium bromide at therapeutic doses or its metabolites do not interact with active substances that are substrates of P-glycoprotein (P-gp), or with active substances metabolized by cytochrome P450 (CYP450) enzymes and esterases (see section "Pharmacokinetics").

Special precautions for use.

Paradoxical bronchospasm.

Use of Bretaris® Genuair® may induce paradoxical bronchospasm. If this occurs, treatment with Bretaris® Genuair® must be discontinued immediately and alternative therapy should be considered.

Worsening of disease condition.

Aclidinium bromide is a maintenance bronchodilator and should not be used to relieve acute bronchospasm attacks, i.e. it is not a rescue medication. If a patient experiences a change in severity of COPD symptoms requiring additional rescue therapy during treatment with aclidinium bromide, the patient's condition and treatment regimen should be reassessed.

Cardiovascular effects.

Cardiac arrhythmias, including atrial fibrillation and paroxysmal tachycardia, have been observed following administration of Bretaris® Genuair® (see section "Adverse reactions"). Therefore, Bretaris® Genuair® should be used with caution in patients with existing cardiac arrhythmias, history of cardiac arrhythmias, or risk factors for cardiac arrhythmias.

Clinical experience in patients with concomitant cardiovascular diseases is limited (see section "Pharmacodynamics"). These conditions may be influenced by the anticholinergic mechanism of action of the medicinal product.

Anticholinergic effects.

Dry mouth, commonly observed during treatment with anticholinergic agents, may contribute to dental caries with prolonged use.

Due to the anticholinergic activity of aclidinium bromide, caution is advised in patients with symptomatic prostatic hyperplasia, bladder neck obstruction, or closed-angle glaucoma (although direct contact of the drug with the eyes is highly unlikely).

Excipients.

This medicinal product contains lactose. Each delivered dose contains approximately 12 mg of lactose (as monohydrate). This medicine should not be administered to patients with rare hereditary forms of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no data on the use of aclidinium bromide in pregnant women.

Animal studies have shown fetal toxicity only at doses greatly exceeding the maximum human exposure to aclidinium bromide (see "Preclinical safety data"). Aclidinium bromide may be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding.

It is unknown whether aclidinium bromide/metabolites are excreted in human breast milk. Animal studies have shown that aclidinium bromide and/or its metabolites are excreted in milk in small amounts. Risk to the newborn/infant cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue/abstain from treatment with Bretaris® Genuair® should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

Animal studies have shown a minor reduction in fertility only at doses greatly exceeding the maximum human exposure to aclidinium bromide (see "Preclinical safety data"). It is considered unlikely that aclidinium bromide administered at the recommended dose would affect fertility in humans.

Ability to influence reaction speed when driving or operating machinery.

Aclidinium bromide may have a minor influence on reaction speed when driving or operating machinery. Headache, dizziness, or blurred vision may occur after administration of aclidinium bromide (see section "Adverse reactions") and may affect the ability to drive or operate machinery.

Method of Administration and Dosage

For inhalation use only.

Patients must be instructed on the correct use of the medicinal product, as the Genuair® inhaler may function differently from inhalers they may have used previously. It is important that the patient carefully reads the instructions for use.

The recommended dose is 1 inhalation of 322 mcg aclidinium twice daily.

If a dose is missed, the next dose should be taken as soon as possible. However, if it is almost time for the next dose, the missed dose should not be administered.

Elderly patients.

Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Renal impairment.

Dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Hepatic impairment.

Dose adjustment is not required in patients with hepatic impairment (see section "Pharmacokinetics").

Instructions for Use

Starting Treatment

Read these instructions for use before starting the medication.

The inhaler is white with an integrated dose indicator and a green dosing button. The mouthpiece is covered by a removable protective cap. The inhaler comes in a laminated plastic pouch, packed in a cardboard box.

Familiarize yourself with the parts of the Genuair® inhaler.

Figure A

Before Use:

• Before first use, open the sealed pouch and remove the inhaler. Discard the pouch.
• Do not press the green button until you are ready to take a dose.
• Remove the cap by gently pressing the arrows marked on each side (Figure B).

Figure B

1.3. Hold the inhaler horizontally, with the mouthpiece facing toward you and the green button facing upward (Figure D).

**

**

Figure D

1.4. Press the green button fully downward to prepare the dose (Figure E).

When you press the button all the way down, the control window changes color from red to green.

Ensure the green button is on top. Do not tilt the inhaler.

1.5. Release the green button (Figure D).

Make sure you release the button so the inhaler can function properly.

Figure E

The dose of medication has not been prepared. Return to section "STEP 1: Prepare the Dose of Medication" and repeat steps 1.1 to 1.6.

STEP 2: Inhale the Medication

Read steps 2.1 to 2.7 completely before using the medication. Do not tilt the inhaler.

2.1. Holding the inhaler away from your mouth, breathe out fully. Never breathe out into the inhaler (Figure F).

Figure F

2.2. Hold your head upright, place the mouthpiece between your lips, and seal your lips tightly around it (Figure G).

Do not hold the green button pressed during inhalation.

Figure G

2.3. Breathe in strongly and deeply through your mouth. Continue inhaling for as long as possible.

If the inhalation is performed correctly, a click will be heard. After hearing the click, continue inhaling for as long as possible. Some patients may not hear the click. Use the control window to confirm that the inhalation was performed correctly.

2.4. Remove the inhaler from your mouth. 2.5. Hold your breath for as long as possible. 2.6. Breathe out slowly, but not into the inhaler.

Some patients may feel a slight graininess in the mouth or a faint sweet or bitter taste. Do not inhale the medication again, even if you do not taste anything or feel no sensation after inhalation.

Stop and Check:

2.7. Make sure the control window is now red (Figure I). This indicates that the medication inhalation was performed correctly.

Figure I

This means the medication inhalation was not performed correctly. Return to section "STEP 2: Inhale the Medication" and repeat steps 2.1 to 2.7.

If the control window still has not turned red, you may have forgotten to release the green button before inhalation, or your inhalation may not have been strong enough. In this case, try again. Make sure you release the green button and breathe out fully. Then take a strong, deep breath through the mouthpiece.

Consult your doctor if, after repeated attempts, the control window remains green.

After each use, replace the protective cap over the mouthpiece (Figure J) to prevent contamination of the inhaler by dust or other substances. If the cap is lost, the inhaler should be discarded.

Additional Information

What to do if you accidentally prepare a dose before use?

Store the inhaler with the protective cap on until the scheduled dose time, then remove the cap and proceed to step 1.6.

How does the dose indicator work?

The dose indicator shows the total number of doses remaining in the inhaler (Figure K).

Each inhaler contains at least 60 doses or at least 30 doses, depending on the pack size.

Each time a dose is prepared by pressing the green button, the dose indicator moves slightly toward the next number (50, 40, 30, 20, 10, or 0).

When do you need a new inhaler?

You need a new inhaler:

• If your inhaler is damaged or if you have lost the cap, or
• When red stripes appear on the dose indicator, indicating that the last dose is approaching (Figure K), or
• When your inhaler is empty (Figure L).

The dose indicator moves gradually from 60 to 0: 60, 50, 40, 30, 20, 10, 0.

How to keep the inhaler clean?

NEVER use water to clean the inhaler, as this may damage the medication.

If you wish to clean it, simply wipe the mouthpiece externally with a dry cloth or paper towel.

Children

The medicinal product Bretaris® Genuair® is not recommended for use in children (under 18 years of age) due to insufficient clinical experience.

Overdose

High doses of aclidinium bromide may cause signs and symptoms of anticholinergic effects. However, a single inhaled dose of up to 6000 mcg of aclidinium bromide in healthy individuals did not result in systemic anticholinergic adverse reactions. Additionally, clinically significant adverse reactions were not observed after 7 days of administration of up to 800 mcg of aclidinium bromide twice daily in healthy individuals.

Acute intoxication following accidental ingestion of aclidinium bromide is unlikely due to its low oral bioavailability and the inhalation delivery mechanism of the Genuair® inhaler.

Adverse Reactions

The most commonly observed adverse reactions during the use of Bretaris® Genuair® are headache (6.6%) and nasopharyngitis (5.5%).

The frequencies of the adverse reactions listed below are based on overall incidence rates of adverse reactions (i.e., reactions occurring in connection with the use of Bretaris® Genuair®). These reactions were observed during the administration of Bretaris® Genuair® at a dose of 322 mcg (636 patients) in one 6-month and two 3-month randomized, placebo-controlled clinical trials, as well as in post-marketing surveillance studies.

In a placebo-controlled study involving 1791 patients with moderate to very severe COPD, in which the treatment duration with Bretaris® Genuair® was up to 36 months, no additional adverse reactions were identified.

Adverse reaction frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

System organ classes	Adverse reactions	Frequency
Infections and infestations	Sinusitis	Common
	Nasopharyngitis	Common
Immune system disorders	Hypersensitivity reactions	Uncommon
	Angioedema	Frequency unknown
	Anaphylactic reaction	Frequency unknown
Nervous system disorders	Headache	Common
	Dizziness	Uncommon
Eye disorders	Blurred vision	Uncommon
Cardiac disorders	Cardiac arrhythmias, including atrial fibrillation and paroxysmal tachycardia	Uncommon
	Tachycardia	Un游戏副本 Reporting of suspected adverse reactions. Reporting adverse reactions after the medicinal product has been registered is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua. Shelf life. 3 years. Use within 90 days after opening. Storage conditions. No special storage conditions required. The Jenuair® inhaler should be stored in its original packaging until first use. Store out of the reach of children. Packaging. 30 doses of powder in an inhaler; 1 inhaler in a plastic pouch in a cardboard box; 60 doses of powder in an inhaler; 1 or 3 inhalers, each in a plastic pouch, in a cardboard box. Prescription status. Prescription only. Manufacturer. Industrias Farmacéuticas Almirall S.A. Manufacturer's address and place of business. Ctra. de Martorell 41-61, 08740 Sant Andreu de la Barca (Barcelona), Spain. Marketing Authorization Holder. Berlin-Chemie AG. Address of the Marketing Authorization Holder. Glienicker Weg 125, 12489 Berlin, Germany.